miR-146a is critical for endotoxin-induced tolerance: IMPLICATION IN INNATE IMMUNITY.
miR-146a is critical for endotoxin-induced tolerance: IMPLICATION IN INNATE IMMUNITY.
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DOI：
10.1074/jbc.m109.056317
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发表时间：
2009-12-11
期刊：
影响因子：
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通讯作者：
Chan EK
中科院分区：
文献类型：
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作者：
Nahid MA;Pauley KM;Satoh M;Chan EK
人toll样受体4 （TLR4）通路在脂多糖（LPS）的作用下被激活，随后的信号转导导致先天免疫细胞产生肿瘤坏死因子-α (TNF-α)等细胞因子。先天免疫反应的缺陷可能导致TNF-α的过量产生，导致全身性炎症和疾病。因此，先天免疫反应需要通过复杂的机制来严格调节，以控制其开始和终止。脂多糖耐受性是对后续脂多糖挑战的低反应状态，是单核细胞在长时间暴露于脂多糖后实现的。在本报告中，内毒素反应性microrna表达分析的动力学揭示了THP-1细胞在LPS刺激后4小时开始miR-146a逐渐增加的独特模式，并在24小时内持续高达35倍。相反，TNF-α在4小时内增加，然后逐渐下降，与miR-146a进展呈负相关。研究了miR-146a在THP-1细胞中对后续LPS攻击的特征性上调。引人注目的是，在THP-1细胞耐受状态下的microRNA表达分析显示，只有miR-146a过表达，表明其在LPS耐受中起重要作用。此外，LPS耐受依赖于LPS启动剂量和相关的miR-146a上调。观察到LPS耐受细胞在去除LPS后22小时恢复对TNF-α产生的反应性，这与miR-146a水平的降低有关。将miR-146a转染到THP-1细胞中模拟LPS的启动，而转染miR-146a抑制剂在很大程度上消除了LPS的耐受性。因此，我们的研究表明，miR-146a对体外单核细胞内毒素耐受至关重要。
The human toll-like receptor 4 (TLR4) pathway is activated in response to lipopolysaccharide (LPS), and subsequent signal transductions lead to the production of cytokines such as tumor necrosis factor-α (TNF-α) by innate immune cells. Defects in innate immune response may contribute to the overproduction of TNF-α leading to systemic inflammation and diseases. Thus, the innate immune response needs to be tightly regulated by elaborate mechanisms to control its onset and termination. LPS tolerance is a state of hyporesponsiveness to subsequent LPS challenge and is achieved by monocytic cells after prolonged exposure to LPS. In this report, kinetics of endotoxin-responsive microRNAs expression analysis revealed a unique pattern of gradual increase for miR-146a starting 4 h after LPS stimulation in THP-1 cells and continued up to 35-fold over 24 h. Conversely, TNF-α increased up to 4 h and then decreased gradually implicating a negative correlation with miR-146a progression. The characteristic up-regulation of miR-146a toward subsequent LPS challenge in THP-1 cells was studied. Strikingly, microRNA expression analysis during the tolerized state of THP-1 cells showed only miR-146a overexpression suggesting its important role in LPS tolerance. In addition, LPS tolerance was dependent on a LPS-priming dose and associated miR-146a up-regulation. LPS-tolerized cells were observed to regain responsiveness in TNF-α production 22 h after LPS removal correlating with a decrease in miR-146a level. Transfection of miR-146a into THP-1 cells mimicked LPS priming, whereas transfection of miR-146a inhibitor largely abolished LPS tolerance. Thus our studies demonstrated that miR-146a is critical for the in vitro monocytic cell-based endotoxin tolerance.